The formulas for the individual amino acids present in Aminosyn–HF 8% are as
follows:

Essential Amino Acids

Isoleucine

CH3CH2CH(CH3)CH(NH2)COOH

Leucine

(CH3)2CHCH2CH(NH2)COOH

Lysine (acetate)

H2N(CH2)4CH(NH2)COOH •
CH3COOH

Methionine

CH3S(CH2)2CH(NH2)COOH

Phenylalanine

CH2CH(NH2)COOH

Threonine

CH3CH(OH)CH(NH2)COOH

Tryptophan

CH2CH(NH2)COOH

Valine

(CH3)2CHCH(NH2)COOH

Nonessential Amino Acids

Alanine

CH3CH(NH2)COOH

Arginine

H2NC(NH)NH(CH2)3CH(NH2)COOH

Cysteine HCl • H20

HSCH2CH(NH2)COOH • HCl • H20

Glycine

H2NCH2COOH

Histidine

CH2CH(NH2)COOH

Proline

Serine

HOCH2CH(NH2)COOH

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.

Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthlate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

DOSAGE AND ADMINISTRATION

The objective of nutritional management of patients with liver disease is the provision of sufficient amino acid and caloric support for proteinsynthesis without exacerbating hepatic encephalopathy.

The total daily dose of Aminosyn-HF 8% (amino acid injection 8%) depends on daily protein requirements and on the patient's metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements. Dosage should also be guided by the patient's fluid intake limits and glucose and nitrogen tolerances, as well as by metabolic and clinical response.

The recommended dosage is 80 to 120 g of amino acids (12 to 18 g of nitrogen) as Aminosyn-HF 8% per day. Typically, 500 mL of Aminosyn-HF 8% appropriately mixed with 500 mL of 50% dextrose supplemented with electrolytes and vitamins is administered over an 8 to 12 hour period. This results in a total daily fluid intake of approximately 2 to 3 liters. Patients with fluid restrictions may only tolerate 1 to 2 liters. Although nitrogen requirements may be higher in severely hypercatabolic or depleted patients, provision of additional nitrogen may not be possible due to fluid intake limits, nitrogen, or glucose intolerance.

In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenousinsulin to prevent hyperglycemia and glycosuria. To prevent reboundhypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose solutions are abruptly discontinued.

Fat emulsion co-administration should be considered when prolonged (more than 5 days) parenteralnutrition is required in order to prevent essential fatty acid deficiency (EFAD). Serumlipids should be monitored for evidence of EFAD in patients maintained on fat-free TPN. Caution should be exercised in administering fat emulsions to patients with severe liver damage. Fat emulsion may obscure the presence of precipitate formation.

The provision of sufficient intracellular electrolytes, principally potassium, magnesium, and phosphate, is required for optimum utilization of amino acids. Approximately 60 to 180 mEq of potassium, 10 to 30 mEq of magnesium, and 10 to 40 mMol of phosphorus per day appear necessary to achieve optimum metabolic response. In addition, sufficient quantities of the major extracellular electrolytes (sodium, calcium, and chloride) must be given. In patients with hyperchloremic or other metabolic acidoses, sodium and potassium may be added as the acetate salts to provide bicarbonateprecursor. The electrolyte content of Aminosyn-HF 8% must be considered when calculating daily electrolyte intake. Serum electrolytes, including magnesium and phosphorus, should be monitored frequently.

Hypertonic mixtures of amino acid and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the superior vena cava. Initial infusion rates should be slow, and gradually increased to the recommended 60 to 125 mL/hour. If the administration rate should fall behind schedule, no attempt to "catch up" to planned intake should be made. In addition to meeting protein needs, the rate of administration, particularly during the first few days of therapy, is governed by the patient's glucose tolerance. Daily intake of amino acids and dextrose should be increased gradually to the maximum required dose as indicated by frequent determinations of glucose levels in blood and urine.

For patients in whom the central venous route is not indicated and who can
consume adequate calories enterally, Aminosyn-HF 8% may be administered by peripheral vein with or without parenteral carbohydrate calories. Such infusates can be
prepared by dilutions of Aminosyn-HF 8% with Sterile Water for Injection, USP
or 5% to 10% dextrose to prepare isotonic or slightly hypertonic solutions for
peripheral infusion. It is essential that peripheral infusion be accompanied
by adequate caloric supplementation.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Care must be taken to avoid incompatible admixtures. Consult with pharmacist.

WARNING:Do not use flexible container in series connections.

HOW SUPPLIED

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive
heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F). [See
USP Controlled Room Temperature.] However, brief exposure up to 40°C
does not adversely affect the product.

SIDE EFFECTS

Reactions reported in clinical studies as a result of infusion of the parenteral fluid were water weight gain, edema, increase in BUN, and dilutional hyponatremia. Asterixis was reported to have worsened in one patient during infusion of the amino acid solution.

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia.

Symptoms may result from an excess or deficit of one or more of the ions present in the solution; therefore, frequent monitoring of electrolyte levels is essential.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.

DRUG INTERACTIONS

No information provided.

Warnings & Precautions

WARNINGS

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store.

Because of the potential for life-threatening events, caution should be taken to ensure that precipitates have not formed in any parenteral nutrient admixture.

This product contains sodium hydrosulfite, a form of sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Safe, effective use of parenteral nutrition requires a knowledge of nutrition
as well as clinical expertise in recognition and treatment of the complications
which can occur. FREQUENT EVALUATIONS AND LABORATORY DETERMINATIONS ARE NECESSARY
FOR PROPER MONITORING OF PARENTERAL NUTRITION. Studies should include blood
sugar, serumproteins, kidney and liver function tests, electrolytes, hemogram,
carbon dioxide content, serum osmolarities, blood cultures, and blood ammonia
levels.

Administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, over-hydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the solutions. The risk of solute overload causing congested states with peripheral and pulmonaryedema is directly proportional to the electrolyte concentrations of the solutions.

WARNING: This product contains aluminum that may be toxic. Aluminum
may reach toxic levels with prolonged parenteral administration if kidney function
is impaired. Premature neonates are particularly at risk because their kidneys
are immature, and they require large amounts of calcium and phosphate solutions,
which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements.

Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.

Special care must be taken when giving hypertonic dextrose to a diabetic or prediabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required.

Peripheral intravenous administration of Aminosyn-HF 8% (amino acid injection 8%) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusions or change infusion site and initiate appropriate treatment.

In patients with myocardial infarct, infusion of amino acids should always be accompanied by dextrose since in anoxia, free fatty acids cannot be utilized by the myocardium, and energy must be produced anaerobically from glycogen or glucose.

Infusion of Aminosyn-HF 8% may not affect the clinical course of patients with fulminant hepatitis who have a poor prognosis and are generally unresponsive to treatment. It has been shown that the abnormalplasma amino acid pattern in fulminant hepatitis differs from that in chronicliver disease.

Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma, and death.

Metabolicacidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum.

Aminosyn-HF 8% has not been adequately studied in pregnant women and children; therefore, its safe use in such patients has not been demonstrated.

To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration.

Use only if solution is clear and container is undamaged. Must not be used
in series connections.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Aminosyn-HF 8% have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.

Pregnancy

Teratogenic Effects: Pregnancy Category C: Animal reproduction
studies have not been conducted with Aminosyn–HF 8%. It is also not known whether
Aminosyn–HF 8% can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Aminosyn–HF 8% should be given to a pregnant
woman only if clearly needed.

Nursing Mothers

Caution should be exercised when Aminosyn–HF 8% is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Aminosyn–HF 8% have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions.

SPECIAL PRECAUTIONS FOR CENTRAL VENOUS NUTRITION

ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.

Central venous nutrition may be associated with complications which can be
prevented or minimized by careful attention to all aspects of the procedure,
including solution preparation, administration, and patient monitoring. IT
IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES,
BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

Although a detailed discussion of the complications is beyond the scope of this insert, the following summary lists those based on current literature.

1. Technical

The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.

2. Septic

The constant risk of sepsis is present during administration of total parenteral nutrition. Since contaminated solutions and infusion catheters are potential sources of infection, it is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.

Solutions should ideally be prepared in the hospital pharmacy in a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.

Consult the medical literature for a discussion of the management of sepsis. In brief, typical management includes replacing the solution being administered with a fresh container and set, and culturing the contents for bacterial or fungal contamination. If sepsis persists and another source of infection is not identified, the catheter is removed, the proximal tip is cultured, and a new catheter reinserted when the fever has subsided. Non-specific, prophylactic antibiotic treatment is not recommended.

Clinical experience indicates that the catheter is likely to be the prime source of infection as opposed to aseptically prepared and properly stored solutions.

Administration time for a single container and set should never exceed 24 hours.

3. Metabolic

The following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, glycosuria, hyperglycemia, hyperosmolar nonketotic states and dehydration, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.

Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma and death.

Overdosage & Contraindications

OVERDOSE

In the event of a fluid or solute overload during parenteraltherapy, re-evaluate
the patient's condition and institute appropriate corrective treatment. See
WARNINGS and PRECAUTIONS.

CONTRAINDICATIONS

Aminosyn-HF 8% (amino acid injection 8%) is contraindicated in patients with anuria, inborn errors of amino acid metabolism, especially those involving branched chain amino acid metabolism such as Maple Syrup Urine Disease and Isovaleric Acidemia, or hypersensitivity to one or more amino acids present in the solution.

The precise mechanisms which produce the therapeutic effects of Aminosyn-HF 8% are not known. The etiopathology of hepatic encephalopathy is also unknown and is thought to be of multifactorial origin. The rationale for Aminosyn-HF 8% is based on observations of plasma amino acid imbalances in patients with liver disease and on theories which postulate that these abnormal patterns are causally related to the development of hepatic encephalopathy.

Clinical studies in patients with hepatic encephalopathy showed that infusion of a solution identical to Aminosyn-HF 8% reversed the abnormal plasma amino acid pattern characterized by decreased levels of branched chain amino acids and elevated levels of aromatic amino acids and methionine. The trend toward normalization of these amino acids was generally associated with an improvement in mental status and EEG patterns. This clinical response was observed in the majority of patients studied. Nitrogen balance was significantly improved and mortality reduced in these typically protein-intolerant patients who received substantial amounts of protein equivalent from the amino acid solution.

Phosphate is a major intracellularanion which participates in providing energy for metabolism of substrates and contributes to significant metabolic and enzymatic reactions in all organs and tissues. It exerts a modifying influence on calcium levels, a buffering effect on acid-base equilibrium, and has a primary role in the renal excretion of hydrogen ions.